Functional imaging of the human dopaminergic midbrain

Düzel, Emrah; Bunzeck, Nico; Guitart-Masip, Marc; Wittmann, Bianca C.; Schott, Björn H.; Tobler, Philippe N.

doi:10.1016/j.tins.2009.02.005

Cited by 199 publications

(194 citation statements)

References 86 publications

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“…Abler et al 2006;Burke et al 2010;Spicer et al 2007;Tobler et al 2007) and more specific predictions of formal learning theories Kahnt et al, 2012;Rutledge et al, 2010;Tobler et al, 2007). However, it is worth keeping in mind that the haemodynamic response measured with neuroimaging is nonspecific rather than a one-to-one reflection of a particular neural event such as dopamine release (see also Düzel et al 2009), which could explain why some fMRI studies have suggested positive coding of losses (Seymour et al 2004; although see also Tom et al 2007) and a dominance of action over value (Guitart-Masip et al, 2012 (Kamin, 1969) used an aversive between-subjects design; by contrast, the experiment described in the text and depicted in abbreviated form here (Waelti et al, 2001) used an appetitive within-subject design where the test consists of a comparison between Y and X (see also Figure 2A); The optogenetic unblocking experiment of Steinberg et al (2013) used a between-subject design.…”

Section: Phasic Dopamine Signals Represent Model-free Prediction Errorsmentioning

confidence: 99%

The role of learning-related dopamine signals in addiction vulnerability

Huys

Tobler

Hasler

et al. 2014

Progress in Brain Research

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Psychostimulants such as methylphenidate (MPH) and antidepressants such as fluoxetine (FLX) are widely used in the treatment of various mental disorders or as cognitive enhancers. These medications are often combined, for example, to treat comorbid disorders. There is a considerable body of evidence from animal models indicating that individually these psychotropic medications can have detrimental effects on the brain and behavior, especially when given during sensitive periods of brain development. However, almost no studies investigate possible interactions between these drugs. This is surprising given that their combined neurochemical effects (enhanced dopamine and serotonin neurotransmission) mimic some effects of illicit drugs such as cocaine and amphetamine. Here, we summarize recent studies in juvenile rats on the molecular effects in the mid-and forebrain and associated behavioral changes, after such combination treatments. Our findings indicate that these combined MPH + FLX treatments can produce similar molecular changes as seen after cocaine exposure while inducing behavioral changes indicative of dysregulated mood and motivation, effects that often endure into adulthood. Tables: 2 References: 254 ABSTRACT Dopaminergic signals play a mathematically precise role in reward-related learning, and variations in dopaminergic signalling have been implicated in vulnerability to addiction. Here, we provide a detailed overview of the relationship between theoretical, mathematical and experimental accounts of phasic dopamine signalling, with implications for the role of learning-related dopamine signalling in addiction and related disorders. We describe the theoretical and behavioural characteristics of model-free learning based on errors in the prediction of reward, including step-by-step explanations of the underlying equations. We then use recent insights from an animal model that highlights individual variation in learning during a Pavlovian conditioning paradigm to describe overlapping aspects of incentive salience attribution and model-free learning. We argue that this provides a computationally coherent account of some features of addiction. CONTENTS

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Section: Phasic Dopamine Signals Represent Model-free Prediction Errorsmentioning

confidence: 99%

The role of learning-related dopamine signals in addiction vulnerability

Huys

Tobler

Hasler

et al. 2014

Progress in Brain Research

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“…Error bars, here and in subsequent figures, depict s.e.m. *P < 0.05. uncorrected height threshold of P< 0.001 and extent threshold of 10 contiguous voxels are presented in Tables 1-3. We consider activation of the entire SN/VTA complex rather than individual components because in humans, mesolimbic and mesocortical dopaminergic projection systems are dispersed throughout the SN/VTA complex (Duzel et al, 2009).…”

Section: Discussionmentioning

confidence: 99%

“…Enhanced memory for novel, or salient, stimuli is thought to be mediated by dopamine via hippocampal inputs from the dopaminergic midbrain (Lisman and Grace, 2005), which comprises the substantia nigra and ventral tegmental area (SN/VTA) (Duzel et al, 2009). In humans, processing of unexpected, salient stimuli can be studied using "oddball" paradigms, in which the oddball stimulus deviates from its prevailing context along a particular dimension.…”

Section: Introductionmentioning

confidence: 99%

“…Long-term human memory for these contextually novel stimuli is enhanced (Ranganath and Rainer, 2003), an effect abolished by hippocampal damage (Kishiyama et al, 2004). A role for dopamine in contextual novelty detection is suggested by human functional magnetic resonance imaging (fMRl) studies demonstrating activation in dopaminergic areas in response to novel oddball stimuli (Bunzeck and Duzel, 2006;Duzel et al, 2009).…”

Section: Introductionmentioning

confidence: 99%

“…The D4 receptor is preferentially expressed in limbic regions, including the hippocampus (Mrzljak et al, 1996), prefrontal cortex (Ariano et al, 1997;Defagot et al, 1997;Matsumoto et al, 1995), and globus pallidus (Mrzljak et al, 1996). Although D4 receptor expression has been shown in primate SN, this is in SN pars reticulata (Mrzljak et al, 1996) and not the SN pars compacta or VTA which contain the majority of dopaminergic neurones in the SN/VTA (Duzel et al, 2009). D4 receptor expression in SN pars compacta has, however, been shown in rodents (Defagot et al, 1997).…”

Section: Introductionmentioning

confidence: 99%

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Dopamine receptor 4 promoter polymorphism modulates memory and neuronal responses to salience

et al. 2014

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Animal models and human functional imaging data implicate the dopamine system in mediating enhanced encoding of novel stimuli into human memory. A separate line of investigation suggests an association between a functional polymorphism in the promoter region for the human dopamine 4 receptor gene (DRD4) and sensitivity to novelty. We demonstrate, in two independent samples, that the -5210T DRD4 promoter polymorphism determines the magnitude of human memory enhancement for contextually novel, perceptual oddball stimuli in an allele dose-dependent manner. The genotype-dependent memory enhancement conferred by the C allele is associated with increased neuronal responses during successful encoding of perceptual oddballs in the ventral striatum, an effect which is again allele dose-dependent. Furthermore, with repeated presentations of oddball stimuli, this memory advantage decreases, an effect mirrored by adaptation of activation in the hippocampus and substantia nigra/ventral tegmental area in C carriers only. Thus, a dynamic modulation of human memory enhancement for perceptually salient stimuli is associated with activation of a dopaminergic-hippocampal system, which is critically dependent on a functional polymorphism in the DRD4 promoter region.

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Effect of Brain Structure, Brain Function, and Brain Connectivity on Relapse in Alcohol-Dependent Patients

Beck

Wüstenberg

Genauck

et al. 2012

Arch Gen Psychiatry

252

242

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Context:In alcohol-dependent patients, brain atrophy and functional brain activation elicited by alcohol-associated stimuli may predict relapse. However, to date, the interaction between both factors has not been studied.Objective: To determine whether results from structural and functional magnetic resonance imaging are associated with relapse in detoxified alcohol-dependent patients.Design: A cue-reactivity functional magnetic resonance experiment with alcohol-associated and neutral stimuli. After a follow-up period of 3 months, the group of 46 detoxified alcohol-dependent patients was subdivided into 16 abstainers and 30 relapsers. Participants: A total of 46 detoxified alcoholdependent patients and 46 age-and sex-matched healthy control subjects Main Outcome Measures: Local gray matter volume, local stimulus-related functional magnetic resonance imaging activation, joint analyses of structural and functional data with Biological Parametric Mapping, and connectivity analyses adopting the psychophysiological interaction approach.Results: Subsequent relapsers showed pronounced atrophy in the bilateral orbitofrontal cortex and in the right medial prefrontal and anterior cingulate cortex, compared with healthy controls and patients who remained abstinent. The local gray matter volume-corrected brain response elicited by alcohol-associated vs neutral stimuli in the left medial prefrontal cortex was enhanced for subsequent relapsers, whereas abstainers displayed an increased neural response in the midbrain (the ventral tegmental area extending into the subthalamic nucleus) and ventral striatum. For alcohol-associated vs neutral stimuli in abstainers compared with relapsers, the analyses of the psychophysiological interaction showed a stronger functional connectivity between the midbrain and the left amygdala and between the midbrain and the left orbitofrontal cortex.Conclusions: Subsequent relapsers displayed increased brain atrophy in brain areas associated with error monitoring and behavioral control. Correcting for gray matter reductions, we found that, in these patients, alcohol-related cues elicited increased activation in brain areas associated with attentional bias toward these cues and that, in patients who remained abstinent, increased activation and connectivity were observed in brain areas associated with processing of salient or aversive stimuli. Psychiatry. 2012;69(8):842-853 Arch Gen

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Functional imaging of the human dopaminergic midbrain

Cited by 199 publications

References 86 publications

The role of learning-related dopamine signals in addiction vulnerability

The role of learning-related dopamine signals in addiction vulnerability

Dopamine receptor 4 promoter polymorphism modulates memory and neuronal responses to salience

Effect of Brain Structure, Brain Function, and Brain Connectivity on Relapse in Alcohol-Dependent Patients

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